The ataxias are a clinically and genetically heterogeneous group of neurodegenerative diseases that variably affect the cerebellum, brainstem, and spinocerebellar tracts. Trinucleotide repeat expansions have been shown to be the mutational mechanism responsible for a number of the ataxias as well as other neurological diseases. The underlying molecular mechanism responsible for the pathology associated with these diseases falls into three broad categories. First, the largest group of triplet repeat diseases are those associated with CAG expansions that are translated into polyglutamine tracts. Diseases caused by polyglutamine expansions include spinal and bulbar muscular atrophy, Huntington's disease, and five different forms of dominantly inherited spinocerebellar ataxias (SCAs). A second group involves the 5′ CCG expansion that causes fragile X mental retardation and the intronic GAA expansion responsible for Friedreich's ataxia. Both of these result in decreased expression of their corresponding protein products. Finally, a third group involves the expanded CTG repeat in the 3′ untranslated region of the dystrophia myotonica-protein kinase coding sequence. This repeat has been shown to cause myotonic dystrophy, but it is not yet understood how this mutation causes an effect at the molecular level.
The ataxias can be dominantly or recessively inherited, or appear with no family history of disease. Among the adult-onset dominant spinocerebellar ataxias (SCAs), seven different loci have been mapped (S. Gispert et al., Nature Genet., 4, 295-299 (1993); Y, Takiyama et al., Nature Genet., 4, 300-304 (1993); K. Gardner et al., Neurology, 44, A361 (1994); S. Nagafuchi et al., Nature Genet., 6, 14-18 (1994); L. P. W. Ranum et al., Nature Genet., 8, 280-284 (1994); A. Benomar et al., Nature Genet., 10, 84-88 (1995); L. G. Gouw et al., Nature Genet., 10, 89-93 (1995); O—. Zhuchenko et al., Nature Genet., 15, 62-69 (1997)). Approximately sixty percent of the dominant ataxias result from expansions in trinucleotide CAG repeats at the SCAT, 2, 3, 6 or 7 loci (S. Nagafuchi et al., Nature Genet., 6, 14-18 (1994); O. Zhuchenko et al., Nature Genet., 15, 62-69 (1997); H. T. On et al., Nature Genet., 4, 211-226 (1993); Y. Kawaguchi et al., Nature Genet., 8, 221-228 (1994); R. Koide et al., Nature Genet., 6, 9-13 (1994); G. Imbert et al., Nature Genet., 14, 285-291 (1996); S.-M. Pulst et al., Nature Genet., 14, 269-276 (1996); K. Sanpei et al., Nature Genet., 14, 277-284 (1996); G. David et al., Nature Genet., 17, 65-70 (1997); M. D. Koob et al., Nature Genet., 18, 72-75 (1998). The substantial clinical variability among the remaining 40% of the genetically undefined dominant families suggests that a number of additional ataxia coding sequences remain to be identified.
Identifying an ataxia coding sequence can provide an improved method for diagnosis of individuals with the disease and increases the possibility of prenatal/presymptomatic diagnosis or better classification of ataxias.